Correlation between expressions of hypoxia -inducible factor (HIF-1α), blood vessels density, cell proliferation, and apoptosis intensity in canine fibromas and fibrosarcomas

Open access


The study aimed to demonstrate the expression of hypoxia-inducible factor (HIF-1α) in soft tissue mesenchymal tumours (fibroma and fibrosarcoma) in dogs. An attempt was made to correlate the obtained results with density of blood vessels (expression of von Willebrand Factor, vWF), expression of Ki-67 proliferation antigen, and with intensity of apoptosis in studied tumours. The study was performed on paraffin sections of 15 fibromas and 40 fibrosarcomas sampled from 55 female dogs aged 6 to 16 years. Immunohistochemical staining against HIF-1α, vWF, and Ki-67 was performed. Apoptosis was detected with the use of TUNEL reaction. A significantly higher HIF-1α expression was noted in fibrosarcomas in comparison to fibromas (P < 0.0001). HIF-1α expression in fibromas manifested strong positive correlation with tumour vascularity (r = 0.67, P = 0.007). Moreover, HIF-1α expression in fibrosarcomas manifested a moderate positive correlation with tumour malignancy grade (r = 0.44, P = 0.004), tumour vascularity (r = 0.52, P < 0.001), Ki-67 antigen expression (r = 0.42; P = 0.007), and TUNELpositive cells (r = 0.37, P = 0.017). Expression of HIF-1α was detected in 86.7% of fibroma type tumours and in 100% of fibrosarcomas. In all studied tumours expression of HIF-1α manifested positive correlation with the density of blood vessels, and in fibrosarcomas it correlated also with malignancy grade, intensity of Ki-67 expression, and with intensity of apoptosis in tumour cells.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Biju M.P. Neumann A.K. Bensinger S.J. Johnson R.S. Turka L.A. Haase V.H.: Vhlh gene deletion induces Hif-1- mediated cell death in thymocytes. Mol Cell Biol 2004 24 9038-9047.

  • 2. Birner P. Gatterbauer B. Oberhuber G. Schindl M. Rössler K. Prodinger A. Budka H. Hainfellner J.A.: Expression of hypoxia-inducible factor-1α in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer 2001 92 165-171.

  • 3. Birner P. Schindl M. Obermair A. Breitenecker G. Oberhuber G.: Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 2001 7 1661-1668.

  • 4. Birner P. Schindl M. Obermair A. Plank C. Breitenecker G. Oberhuber G.: Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000 60 4693-4596.

  • 5. Blouw B. Song H. Tihan T. Bosze J. Ferrara N. Gerber H.P. Johnson R.S. Bergers G.: The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 2003 4 133-146.

  • 6. Bos R. Zhong H. Hanrahan C.F. Mommers E.C. Semenza G.L. Pinedo H.M. Abeloff M.D. Simons J.W. van Diest P.J. van der Wall E.: Levels of hypoxia-inducible factor-1α during breast carcinogenesis. J Natl Cancer Inst 2001 93 309-314.

  • 7. Carmeliet P. Dor Y. Herbert J.M. Fukumura D. Brusselmans K. Dewerchin M. Neeman M. Bono F. Abramovitch R. Maxwell P. Koch C.J. Ratcliffe P. Moons L. Jain R.K. Collen D. Keshert E.: Role of HIF-1α in hypoxia-mediated apoptosis cell proliferation and tumour angiogenesis. Nature 1998 394 485-490.

  • 8. Ciaputa R. Kandefer-Gola M. Nowak M. Madej J.A.: Prevalence of tumours in domestic animals in the Lower Silesia (Poland) in 2009-2011. Bull Vet Inst Pulawy 2013 57 53-59.

  • 9. Francis P. Namløs H.M. Müller C. Edén P. Fernebro J. Berner J.M. Bjerkehagen B. Akerman M. Bendahl P.O. Isinger A. Rydholm A. Myklebost O. Nilbert M.: Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics 2007 8 73-89.

  • 10. Guo K. Searfoss G. Krolikowski D. Pagnoni M. Franks C. Clark K. Yu K.T. Jaye M. Ivashchenko Y.: Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell Death Differ 2001 8 367-376.

  • 11. Haberkorn U. Altmann A. Mier W. Eisenhut M.: Molecular imaging of tumor metabolism and apoptosis. Ernst Schering Found Symp Proc 2007 4 125-152.

  • 12. Jiang C.Q. Fan L.F. Liu Z.S. Qian Q. Xia D. Diao L.M. He Y.M. Ai Z.L.: Expression levels and significance of hypoxia inducible factor-1α and vascular endothelial growth factor in human colorectal adenocarcinoma. Chin Med J 2004 117 1541-1546.

  • 13. Jiang C.Q. Liu Z.S. Qian Q. He Y.M. Yuan Y.F. Ai Z.L.: Relationship of hypoxia-inducible factor 1α (HIF-1α) gene expression with vascular endothelial growth factor (VEGF) and microvessel density (MVD) in human colorectal adenoma and adenocarcinoma Ai Zheng. 2003 22 1170-1174.

  • 14. Kang T. Ye F.C. Gao S.J. Wang L.D.: Angiogenesis Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus. Virol Sin 2008 23 449-458.

  • 15. Kilic M. Kasperczyk H. Fulda S. Debatin K.M.: Role of hypoxia inducible factor-1α in modulation of apoptosis resistance. Oncogene 2007 26 2027-2038.

  • 16. Koukourakis M.I. Giatromanolaki A. Skarlatos J. Corti L. Blandamura S. Piazza M. Gatter K.C. Harris A.L.: Hypoxia inducible factor (HIF-1α and HIF-2α) expression in early oesophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res 2001 61 1830-1832.

  • 17. Maxwell P.H.: The HIF pathway in cancer. Seminars Cell Develop Biol 2005 16 523-530.

  • 18. Ozbudak I.H. Karaveli S. Simsek T. Erdogan G. Pestereli E.: Neoangiogenesis and expression of hypoxia-inducible factor 1α vascular endothelial growth factor and glucose transporter-1 in endometrioid type endometrium adenocarcinomas. Gynecol Oncol 2008 108 603-608.

  • 19. Remmele W. Stegner H.E.: Vorschlag zur einheitlichen Definition eines immunoreaktiven Score (IRS) für den immunohistochemichen Östrogenrezeptor-Nachweis (ER-ICA) im Mammakarzinomgewebe. Pathologie 1987 8 138-140.

  • 20. Savai R. Schermuly R.T. Voswinckel R. Renigunta A. Reichmann B. Eul B. Grimminger F. Seeger W. Rose F. Hänze J.: HIF-1α attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model. Int J Oncol 2005 27 393-400.

  • 21. Semenza G.L.: HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 2002 8 62-67.

  • 22. Shintani K. Matsumine A. Kusuzaki K. Matsubara T. Satonaka H. Wakabayashi T. Hoki Y. Uchida A.: Expression of hypoxia-inducible factor (HIF)-1α as a biomarker of outcome in soft-tissue sarcomas. Virchows Arch 2006 449 673-81.

  • 23. Shyu K.G. Hsu F.L. Wang M.J. Wang B.W. Lin S.: Hypoxia- inducible factor 1α regulates lung adenocarcinoma cell invasion. Exp Cell Res 2007 313 1181-1191.

  • 24. Simiantonaki N. Taxeidis M. Jayasinghe C. Kurzik-Dumke U. Kirkpatrick C.J.: Hypoxia-inducible factor 1α expression increases during colorectal carcinogenesis and tumor progression. BMC Cancer 2008 4 320-333.

  • 25. Staab A. Loeffler J. Said H.M. Diehlmann D. Katzer A. Beyer M. Fleischer M. Schwab F. Baier K. Einsele H. Flentje M. Vordermark D.: Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 2007 7 213-220.

  • 26. Sun H.C. Qiu Z.J. Liu J. Sun J. Jiang T. Huang K.J. Yao M. Huang C.: Expression of hypoxia-inducible factor-1α and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol 2007 30 1359-1367.

  • 27. Urano N. Fujiwara Y. Doki Y. Tsujie M. Yamamoto H. Miyata H. Takiguchi S. Yasuda T. Yano M. Monden M.: Overexpression of hypoxia-inducible factor-1α in gastric adenocarcinoma. Gastric Cancer 2006 9 44-49.

  • 28. Webb C.P. Van de Woude G.F.: Genes that regulate metastases and angiogenesis. J Neurooncol 2000 50 71-87.

  • 29. Weiss S.W. Goldblum J.R.: Soft Tissue Tumors. Mosby St. Louis 2001 pp. 21-44.

  • 30. Zhong H. De Marzo A.M. Laughner E. Lim M. Hilton D.A. Zagzag D. Buechler P. Isaacs W.B. Semenza G.L. Simons J.W.: Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999 59 5830-5835.

Journal information
Impact Factor

IMPACT FACTOR 2018: 0,829
5-year IMPACT FACTOR: 0,938

CiteScore 2018: 0.68

SCImago Journal Rank (SJR) 2018: 0.291
Source Normalized Impact per Paper (SNIP) 2018: 0.501

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 181 97 3
PDF Downloads 88 56 3